1. Field of the Invention
The present invention is broadly concerned with anti-thrombotic morpholino-substituted compounds and corresponding methods of use. More particularly, the present invention relates to morpholino-substituted pyridopyrimidine, quinolone, and benzopyranone derivatives which inhibit the enzyme phosphoinositide (PI) 3-kinase, and which are useful in treating PI 3-kinase-dependent conditions, including cardiovascular diseases, respiratory diseases, inflammatory disorders, neoplasms such as cancers, and diseases linked to disordered white blood cell function.
2. Description of the Related Art
Cell-adhesion interactions are crucial for a broad range of physiological processes, including inflammation, immunity, and hemostasis. Platelets are specialized adhesive cells which play a fundamental role in the hemostatic process. Upon vascular injury, platelets adhere to specific subendothelial adhesive proteins, such as von Willebrand factor (vWF). The binding of vWF to its specific receptor on the platelet surface, glycoprotein (GP) Ib/V/IX, induces platelet activation and cytoskeletal reorganization. These cytoskeletal changes result in filopodial extension and the formation of lamellipodial sheets, which are essential processes for platelet spreading and the formation of the primary hemostatic platelet plug.
An exaggerated platelet adhesion response at sites of atherosclerotic plaque rupture commonly leads to the formation of vaso-occlusive platelet thrombi. The formation of these thrombi in the coronary or cerebral circulation leads to heart attacks and strokes, respectively, which combined represent the leading causes of death in the industrialized world. Platelet thrombus formation also leads to a number of other clinical states including unstable angina, sudden death, transient ischemic attacks, amaurosis fugax, and acute ischemia of limbs and internal organs.
Undesirable thrombosis also may be associated, however, with invasive medical procedures such as cardiac surgery (e.g., angioplasty), abdominothoracic surgery, arterial surgery, deployment of an implementation (e.g., a stent or catheter), and endarterectomy. Furthermore, thrombosis may accompany various thromboembolic disorders and coagulopathies such as a stroke, pulmonary embolism (e.g., atrial fibrillation with embolization) and disseminated intravascular coagulation. An unwanted thrombus also can arise from manipulation of body fluids, as occurs in the context of blood transfusion or fluid sampling, as well as in procedures involving extracorporeal circulation (e.g., cardiopulmonary bypass surgery) and dialysis.
Anti-coagulants and anti-platelet agents are frequently used to alleviate thrombosis. Blood clotting can be minimized or eliminated in many instances by administering a suitable anti-coagulant, including one or more of a coumarin derivative (e.g., warfarin and dicumarol) or a charged polymer (e.g., heparin, hirudin or hirulog), or through the use of an anti-platelet agent (e.g., aspirin, clopidogrel, ticlopidine, dipyridimole, or one of several GPIIb/IIIa receptor antagonists). But anticoagulants and platelet inhibitors can have side effects such as hemorrhaging, re-occlusion, “white-clot” syndrome, irritation, birth defects, thrombocytopenia, and hepatic dysfunction. Moreover, long-term administration of anti-coagulants and platelet inhibitors can particularly increase risk of life-threatening illness or hemorrhage.